Quinine

Absorption

76 - 88%

Toxicity

Quinine is a documented causative agent of drug induced thrombocytopenia (DIT). Thrombocytopenia is a low amount of platelets in the blood. Quinine induces production of antibodies against glycoprotein (GP) Ib-IX complex in the majority of cases of DIT, or more rarely, the platelet-glycoprotein complex GPIIb-IIIa. Increased antibodies against these complexes increases platelet clearance, leading to the observed thrombocytopenia.

Description

Quinine, was the first known antimalarial. It is a 4-quinolinemethanol derivative bearing a substituted quinuclidine ring. The use of quinine in Europe began in the seventeenth century, after the Incas of Peru informed the Spanish Jesuits about the antimalarial properties of the bark of an evergreen mountain tree they called quinquina (later called cinchona, after Dona Franciscoa Henriquez de Ribera [1576–1639], Countess of Chinchon and wife of the Peruvian Viceroy).

Description

Quinine, is an extract from the bark of the cinchona tree that has been used for more than three hundred years as an anti-malarial.?Woodward—Doering/Rabe—Kindler total synthesis?of quinine ushered in the modern era of synthetic organic chemistry. The first stereoselective synthesis was reported in 2001.

Chemical properties

white to light yellow crystal powde

Chemical properties

Quinine is odorless, but has an intense, bitter taste

Physical properties

Appearance: white granular or microcrystalline powder. No smell, slightly bitter. Solubility: easily dissolved in ethanol, chloroform, and ethyl. Slightly soluble in water and glycerol. Melting point: 173–175 °C. Specific optical rotation: ?172° (ETOH, C = 1).

Occurrence

Reported present in Cinchona officinalis.

History

Quinine is a white crystalline alkaloid best known for treating malaria. Quinine is derived from the bark of several species of trees in the genus Cinchona in the Rubiaceae family. Cinchona trees grow on the eastern slopes of the Andes Mountains at elevations of several thousand feet. Because these symptoms were associated with malaria, Cinchona bark powder was recognized as a possible treatment in the 1600s by Jesuit missionaries.
After decades of work by numerous investigators, quinine was finally isolated in 1820 by Pierre-Joseph Pelletier (1788–1842) and Joseph-Bienaimé Caventou (1795–1877). The name quinine originates from the native word for the Cinchona tree quina quina, which became the Spanish word quino for cinchona. The development of organic synthesis in the middle of the 19th century and the limited supply of quinine stimulated attempts to synthesize it. William Henry Perkins’s (1838–1907) attempt to synthesize quinine in 1856 led to his discovery of mauve, which was a signifi cant discovery in the dye industry (see Indigo).

The Uses of Quinine

Because of its relatively constant and well-known fluorescence quantum yield, quinine is also used in photochemistry as a common fluorescence standard. It has been used for imaging of oxygen evolution and oxide formation. Chloride and bromide have been sh

The Uses of Quinine

Primary alkaloid of various species of Cinchona (Rubiaceae). Optical isomer of Quinidine. Antimalarial; muscle relaxant (skeletal)

The Uses of Quinine

antimalarial, skeletal muscle relaxant

The Uses of Quinine

Quinine is a flavorant naturally obtained from the cinchona tree. it is used as a bitter flavoring in beverages such as quinine water, tonic water, and bitter lemon. quinine sulfate and quinine hydrochloride are cleared for use as a flavor in carbonated beverages at levels less than 83 ppm.

The Uses of Quinine

Quinine occurs in the dried stems or rootbarks of cinchona (Cinchona ledgerianaMoens). It is used in the treatment of malaria.It is also used as an analgesic and antipyreticagent.

The Uses of Quinine

Quinines use as an antimalarial agent spans several hundred years, but it has been replaced in recent years by other substances such as chloroquine. Because some Plasmodium strains have developed resistance to several malaria medications, quinine use is being revived. About 60% of quinine production is used for medicinal purposes, and the drug is available by prescription. In addition to its use as an antimalarial agent, quinine medications are used to treat leg cramps, muscle cramps associated with kidney failure, hemorrhoids, heart palpitations, and as an analgesic. At higher concentrations it is toxic and causes a condition known as cinchonism. Conditions associated with cinchonism include dizziness, hearing loss, visual impairment, nausea, and vomiting.
Nonmedicinal use of quinine, accounting for about 40% of its use, is primarily as a fl avoringagent in condiments and liqueurs. The most common food use of quinine is tonic water. Tonicwater originated in India where English colonists drank carbonated water mixed with quinineto prevent malaria. The bitter taste of quinine was often masked by mixing it with alcoholicbeverages; one result of this practice was the drink gin and tonic. Current Food and DrugAdministration regulations in the United States limit the amount of quinine in tonic water to83 parts per million (83 mg per liter). This level is signifi cantly less than that required for therapeuticpurposes, so the use of commercial tonic waters to combat malaria is not practical.

Background

An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood.

Indications

For the treatment of malaria and leg cramps

What are the applications of Application

Quinine is an antimalarial

Definition

ChEBI: A cinchona alkaloid that is cinchonidine in which the hydrogen at the 6-position of the quinoline ring is substituted by methoxy.

Definition

A poisonous ALKALOID found in the bark of the cinchona tree of South America. It is used in treating malaria.

Definition

quinine: A white solid,C₂₀H₂₄N₂O₂·3H₂O, m.p. 57°C. It is apoisonous alkaloid occurring in thebark of the South American cinchonatree, although it is now usually producedsynthetically. It forms saltsand is toxic to the malarial parasite,and so quinine and its salts are used to treat malaria; in small doses itmay be prescribed for colds and influenza.In dilute solutions it has apleasant astringent taste and is addedto some types of tonic water.

Indications

Quinine is one of several alkaloids derived from the bark of the cinchona tree. The mechanism by which it exerts its antimalarial activity is not known. It does not bind to DNA at antimalarial dosages. It may poison the parasite’s feeding mechanism, and it has been termed a general protoplasmic poison, since many organisms are affected by it.
Quinine is rapidly absorbed following oral ingestion, with peak blood levels achieved in 1 to 4 hours. About 70 to 93% of the drug is bound to plasma proteins, depending on the severity of the infection. Quinine is extensively metabolized, with only about 20% of the parent compound eliminated in the urine.
The primary present-day indication for quinine and its isomer, quinidine, is in the intravenous treatment of severe manifestations and complications of chloroquine- resistant malaria caused by P. falciparum.
Aside from its use as an antimalarial compound, quinine is used for the prevention and treatment of nocturnal leg muscle cramps, especially those resulting from arthritis, diabetes, thrombophlebitis, arteriosclerosis, and varicose veins.

Preparation

By reaction from cinchona bark (Cinchona officinalis), where it is present at approximately 8%.

Antimicrobial activity

Quinine inhibits the erythrocytic stages of human malaria parasites at <1 mg/L, but not the liver stages. It is active against the gametocytes of P. vivax, P. ovale and P. malariae, but not P. falciparum. The dextrarotatory stereoisomer, quinidine, is more active than quinine, but epiquinine (cinchonine) and epiquinidine (cinchonidine) have much lower antimalarial activities.

Acquired resistance

Resistance is now widespread in South East Asia, where some strains are also resistant to chloroquine, sulfadoxine– pyrimethamine and mefloquine. Cross-resistance with mefloquine has been demonstrated in P. falciparum, but genetic polymorphisms associated with chloroquine resistance are not associated with quinine resistance.

General Description

Quinine, a cinchona alkaloid found in the bark of the cinchona tree, is known for its anti-malarial property.

Hazard

Skin irritant, ingestion of pure substance adversely affects eyes.

Health Hazard

The toxicity of quinine is characterized bycinchonism, a term that includes tinnitus,vomiting, diarrhea, fever, and respiratorydepression. Other effects include stimulationof uterine muscle, analgesic effect,and dilation of the pupils. Severe poisoningmay produce neurosensory disorders, causingclouded vision, double vision, buzzing of theears, headache, excitability, and sometimescoma (Ferry and Vigneau 1983). Death fromquinine poisoning is unusual. Massive dosesmay be fatal, however.
LD50 value, oral (guinea pigs): 1800 mg/kg.

Flammability and Explosibility

Non flammable

Pharmaceutical Applications

A quinolinemethanol from the bark of the Cinchona tree; the laevorotatory stereoisomer of quinidine. Formulated as the sulfate, bisulfate or ethylcarbonate for oral use and as the dihydrochloride for parenteral administration. The salts are highly soluble in water.

Biochem/physiol Actions

Potassium channel blocker

Pharmacokinetics

Quinine is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.

Pharmacokinetics

Oral absorption: 80–90%
C_max 600 mg oral: 5 mg/L after 1–3 h
Plasma half-life: 8.7 h
Volume of distribution: 1.8 L/kg
Plasma protein binding: c. 70%
Quinine is well absorbed by the oral route. Intramuscular administration gives more predictable data than intravenous administration and may be more useful in children. Plasma protein binding rises to 90% in uncomplicated malaria and 92% in cerebral malaria due to high levels of acute-phase proteins. Similarly, the elimination half-life rises to 18.2 h in severe malaria. There is extensive hepatic metabolism to hydroxylated derivatives. Urinary clearance is <20% of total clearance.

Pharmacology

In terms of its type of action, quinine is an antimalarial drug similar to chloroquine, although it is inferior in its activity.
Like chloroquine, quinine binds with plasmodium DNA, thus interfering in the synthesis of nucleic acids and preventing its replication and transcription. Quinine also suppresses a large portion of the enzymatic system and therefore it is characterized as a general protoplasmid toxin. This fact agrees well with the action of quinine on membranes, its local anesthetizing and its cardiodepressive effects.
Upon oral administration, quinine effectively acts in combination with pyrimethamine, sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquineresistant forms of P. falciparum. Because of the many associated side effects, its use is extremely limited. Currently, the only indication for use is for forms of malaria that are resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv, quinnam, and others.

Clinical Use

Falciparum malaria (alone or in combination with tetracycline, doxycycline, clindamycin or pyrimethamine–sulfadoxine)
Babesiosis (in combination with clindamycin)
It is particularly used in cerebral malaria if chloroquine resistance is suspected (Ch. 62). It is not recommended for treatment of uncomplicated falciparum malaria.

Side Effects

Up to 25% of patients experience cardiac dysrhythmia, hypoglycemia, cinchonism (tinnitus, vomiting, diarrhea, headache). Severe effects, including hypotension and hypoglycemia, are of particular importance in children, pregnant women and the severely ill. Rarely, it can induce hemolytic anemia (‘blackwater fever’). Quinine inhibits tryptophan uptake into cells.

Side Effects

Cinchonism describes the toxic state induced by excessive plasma levels of free quinine. Symptoms include sweating, ringing in the ears, impaired hearing, blurred vision, nausea, vomiting, and diarrhea. Quinine is a potent stimulus to insulin secretion and irritates the gastrointestinal mucosa. Also, a variety of relatively rare hematological changes occur, including leukopenia and agranulocytosis. Quinine is potentially neurotoxic in high dosages, and severe hypotension may follow its rapid intravenous administration.

Safety Profile

Human poison by unspecified route. Experimental poison by subcutaneous, intravenous, intramuscular, and intraperitoneal routes. Moderately toxic experimentally by ingestion. An experimental teratogen. Human systemic effects by ingestion: visual field changes, tinnitus, and nausea or vomiting. Human teratogenic effects by ingestion: developmental abnormahties of the central nervous system, body wall, and musculoskeletal, cardovascular, and hepatoblltary systems. Experimental reproductive effects. Mutation data reported. Can cause temporary loss of vision. Quinine dermatitis is an occupational hazard to barbers particularly, and generally to people who work with quinine tonics, medcaments, or cosmetics. An irritant to mucous membranes. Combustible when exposed to heat or flame. Decomposes on exposure to light. When heated to decomposition it emits toxic fumes of NOx. Used to treat malaria.

Synthesis

Quinine, (5-vinyl-2-quinuclidinyl)-(6-methoxy-4-quinolyl)methanol (37.1.1.47), is isolated from the bark of the cinchona tree. One of the methods of making the ethyl ester of quininic acid (37.1.1.27) that should be mentioned is the method described in the following scheme. Reacting p-anisidine and acetoacetic ester in the presence of sulfuric acid gives 6-methoxylepidine (37.1.1.22). The hydroxyl group of this compound is replaced with a chlorine atom by reacting it with a mixture of phosphorus oxychloride and phosphorus pentachloride, giving 2-chloro- 4-methyl-6-methoxyquinoline (37.1.1.23). Reducing this compound with hydrogen using a palladium catalyst removes the chlorine atom at C2 and gives 4-methyl- 6-methoxyquinoline (37.1.1.24). Condensing this with benzaldehyde gives 2-(6-methoxy quinolinyl-4)-styrene (37.1.1.25), the double bond in which is oxidized using potassium permanganate to make 6-methoxyquinolinic acid—cinchonine (37.1.1.26), which is then converted into an ester (37.1.1.27) in the usual manner.

Another convenient way for preparation of quininic acid ethyl ester (37.1.1.27) is by using p-N-methylacetanisidine and diethyloxalate, which are reacted to form the p-N-methylacetaniside of oxalacetic acid (37.1.1.28). Heterocyclization of the product under acidic conditions leads to the formation of N-methyl-2-keto-4-carbethoxy-6-methoxyquinoline (37.1.1.29), which is reacted with a mixture of phosphorus oxychloride and phosphorus pentachloride to make 2-chloro-4-carboethoxy-6-methoxyquiniline (37.1.1.30). Reducing this with hydrogen using a palladium catalyst gives ethyl ester of 6-methoxyquinolinic acid (37.1.1.27).

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: flecainide levels increased; increased risk of ventricular arrhythmias with amiodarone - avoid.
Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin - avoid; concentration reduced by rifampicin.
Antidepressants: possible increased risk of ventricular arrhythmias with citalopram and escitalopram.
Antimalarials: increased risk of convulsions with mefloquine; avoid concomitant use with artemether/ lumefantrine.
Antipsychotics: increased risk of ventricular arrhythmias with droperidol, pimozide, risperidone and possibly haloperidol - avoid.
Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir and tipranavir; concentration increased by ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid.
Cardiac glycosides: levels of digoxin increased (halve maintenance dose).
Ciclosporin: decreased ciclosporin levels reported.
Cimetidine: may increase plasma levels of quinine.

Metabolism

Hepatic, over 80% metabolized by the liver.

Metabolism

Quinine is metabolized in the liver to the 2′-hydroxy derivative, followed by additional hydroxylation on the quinuclidine ring, with the 2,2′-dihydroxy derivative as the major metabolite. This metabolite has low activity and is rapidly excreted. The metabolizing enzyme of quinine is CYP3A4. With the increased use of quinine and its use in combination with other drugs, the potential for drug interactions based on the many known substrates for CYP3A4 is of concern.

Purification Methods

Crystallise the quinine from absolute EtOH. It has been used as a chiral catalyst (see previous entry). [Beilstein 23 H 511, 23 I 166, 23 II 416, 23 III/IV 3265, 23/13 V 395.]

References

Pelletier, Dumas., Ann. Chim. Phys., 15,291,1337 (1820)
Hesse., Annalen, 258, 133 (1890)
Fiihner., Arch. Pharm., 244, 602 (1906)
Seekles., Rev. Trav. Chim., 42, 72 (1923)
Kindler., Chem. Ztg., 56, 165 (1932)
Cohen.,J. Chem. Soc., 999 (1933)
Velter., Festschrift., 542 (Basle, 1936)
Woodward, Doering.,J. Amer. Chem. Soc., 67,860 (1945)
Pharmacology :
Acton, King., Biochem. J., 15,53 (1921)
Sterkin, Helfgat., Biochem. Zeit., 207, 8 (1929)
Wagenaar.,Pharm. Weekbl., 66, 177, 197,250,261 (1929)
Wagenaar., ibid, 71,316 (1934)
Monnet., J. Pharm. Chim., 18, 94 (1933)
Buttle, Henry, Trevan., Biochem. J., 28,426 (1934)
Seeler, Dusenbery, Malanga.,J. Pharm. Exp. Ther., 78, 159 (1943)
Marshall., ibid, 85, 299 (1945)